S272: SAFETY AND PRELIMINARY PHARMACODYNAMIC EFFECTS OF THE FERROPORTIN INHIBITOR VAMIFEPORT (VIT-2763) IN PATIENTS WITH NON-TRANSFUSION-DEPENDENT BETA THALASSEMIA (NTDT): RESULTS FROM A PHASE 2A STUDY
Authors: A. Taher, A. Kourakli-Symeonidis, A. Tantiworawit, P. Wong, P. Szecsödy
Journal: HemaSphere (2022)

Background: NTDT is characterized by an imbalanced α/β-globin chain ratio, ineffective erythropoiesis, increased intestinal iron absorption and iron overload. Vamifeport inhibits ferroportin-mediated iron export into plasma and has been shown to decrease serum iron and transferrin saturation (TSAT) levels in relevant animal disease models and healthy volunteers. Aims: The primary objective of this multicenter, Phase 2a, double-blind, randomized, placebo-controlled study (NCT04364269) was to assess the safety and tolerability of vamifeport (given once [QD] or twice [BID] daily) versus placebo in patients with NTDT over a 12-week treatment period. A secondary objective was to assess preliminary efficacy of vamifeport versus placebo with respect to pharmacodynamic effects on iron parameters (serum iron, ferritin, hepcidin and TSAT) in these patients. Methods: Adults (18–65 years) with documented NTDT (including β-thalassemia intermedia) who provided informed consent, were included. NTDT was defined as receipt of <5 units of red blood cells during the 24 weeks prior to randomization. Patients also required a mean baseline hemoglobin of ≤11 g/dL on two consecutive measurements ≥1 week apart within 6 weeks prior to randomization. Use of iron chelation therapy (ICT) within 4 weeks prior to randomization was not permitted; patients with TSAT <30%, serum ferritin <150 ng/mL and/or liver iron content ≤1 mg/g (<300 ng/mL/3 mg/g, respectively, for those recently on ICT) were also excluded. Patients received vamifeport at a dose of 60 mg if their body weight was 40–59 kg or 120 mg if their weight was 60–100 kg. Results: Twenty-five patients were included (vamifeport QD n=9, BID n=12, placebo n=4; median age 42.0, 31.0 and 40.5 [range 18–61] years, respectively). Overall, 64% were male, 56% had a body weight <60 kg and 16% had received prior ICT. At baseline, mean (standard deviation [SD]) serum iron concentrations were 27.2 (11.6) µmol/L and mean TSAT was 76.2 (27.6)% for the population as a whole. Mean (SD) serum ferritin concentrations were 746.7 (1431.7) µg/L. There were no differences between groups in treatment-emergent adverse event (TEAE) rates (vamifeport QD 66%, BID 58%; placebo 75%). All TEAEs were mild or moderate intensity, and each was reported only once. There were no deaths or serious AEs (1 patient receiving vamifeport QD had an acute hemolytic event); one TEAE (increased creatine kinase and transaminase levels, not drug-related) led to drug discontinuation in the vamifeport BID group. There were also no clinically relevant changes in any assessed safety parameter. Serum iron concentrations decreased 3 h after first vamifeport dose (Day 1) in all vamifeport-treated patients (mean [SD] decrease: QD -11.3 [7.2] µmol/L; BID -17.0 [9.6] µmol/L) and were maintained below baseline levels at 3–4 h post vamifeport administration at each visit throughout the remaining treatment period. Mean (SD) TSAT also decreased at Day 1 (3 h post dose; QD -32.6 [19.6]%; BID -46.8 [22.6]%) and were below baseline levels 3–4 h post-dose at each subsequent visit in the vamifeport groups (Figure). There were no clinically meaningful changes from baseline in serum iron or TSAT levels in the placebo group, or in ferritin or hepcidin levels in any treatment group. Image:Summary/Conclusion: In this 12-week Phase 2a study, vamifeport had a favorable safety and tolerability profile and showed promising target engagement and pharmacodynamic effects on serum iron and TSAT levels versus placebo in adults with NTDT.